Fli-1 Is Required for Murine Vascular and Megakaryocytic Development and Is Hemizygously Deleted in Patients with Thrombocytopenia

Abstract

The ETS gene Fli-1 is involved in the induction of erythroleukemia in mice by Friend murine leukemia virus and Ewings sarcoma in children. Mice with a targeted null mutation in the Fli-1 locus die at day 11.5 of embryogenesis with loss of vascular integrity leading to bleeding within the vascular plexus of the cerebral meninges and specific downregulation of Tek/Tie-2, the receptor for angiopoietin-1. We also show that dysmegakaryopoiesis in Fli-1 null embryos resembles that frequently seen in patients with terminal deletions of 11q (Jacobsen or Paris-Trousseau Syndrome). We map the megakaryocytic defects in 14 Jacobsen patients to a minimal region on 11q that includes the Fli-1 gene and suggest that dysmegakaryopoiesis in these patients may be caused by hemizygous loss of Fli-1.

Persistent Down-Regulation of Fli1, a Suppressor of Collagen Transcription, in Fibrotic Scleroderma Skin

“…Furthermore, it was demonstrated that Fli1 Ϫ/Ϫ endothelial cells were not viable even in the chimeric embryos consisting of Fli1 ϩ/ϩ and Fli1 Ϫ/Ϫ cells. 23 These previous studies demonstrate that Fli1 plays a critical role in endothelial cell function during embryogenesis. Presence of Fli1 in endothelial cells in healthy skin suggests that it may also have an important function in adult tissues.…”

“…1,44 Fli1 is known to play an essential, although not fully defined, role in endothelial cell function. 22,23 Mice with a targeted mutation in Fli1 locus, die of hemorrhage at day 11.5 of embryogenesis because of , at least in part, the loss of vascular integrity. Interestingly, Fli1 Ϫ/Ϫ embryos are able to form a functional network of blood vessels, but appear to fail to recruit pericytes or smooth muscle cells during late embryonic angiogenesis and vascular remodeling.…”

“…20 Fli1, a member of the Ets family of transcription factors, has been shown to play roles in hematopoiesis, embryonic development, and vasculogenesis. [21][22][23][24] Collective evidence indicates that Ets transcription factors are the important mediators of cellular programs involved in extracellular matrix degradation, 25 and are frequently dysregulated in diseases characterized by abnormal matrix turnover, including invasive tumors and arthritis. 26 In contrast, the specific role(s) of the Ets factors in the maintenance of collagen level homeostasis in healthy skin and their possible role in fibroproliferative disorders, including SSc, has not yet been adequately assessed.…”

Ets proteins in biological control and cancer

“…Furthermore, specific in vivo targets for Ets genes have been identified based on the knockout mice: for example, c-mpl [Kawada et al, 2001] and Tie2 [Hart et al, 2000] have reduced expression in knockout Fli1 mice. Third, it is becoming increasingly evident that cellular context defines the direction and magnitude of response to Ets factors.…”

Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

“…Murine Fli1 was first identified as a proto-oncogene as a site for retroviral integration of Friend virus-induced erythroleukemias (Ben-David et al, 1990). It is expressed in hematopoietic tissues in both embryos and adults, as well as in other tissues (Ben-David et al, 1991;Melet et al, 1996;Watson et al, 1992) and is essential for embryogenesis (Hart et al, 2000;Masuya et al, 2005;Spyropoulos et al, 2000). During lymphocyte development, Fli1 is first detected in the developing spleen and thymus of the embryo and later in mature B cells and throughout T cell development (Anderson et al, 1999;Melet et al, 1996), but is down-regulated in activated T cells (Mao et al, 1994;Zhang and Watson, 2005).…”